The NEIGHBORHOOD: POAG Heritable Overall Operational Database

描述（由申请人提供）：原发性开角型青光眼（POAG）是全球范围内致盲的重要原因。原发性开角型青光眼的病因尚不清楚，无法进行一级预防。 目前的治疗可以减缓但不能治愈这种进行性神经病。 我们研究的总体目标是阐明原发性开角型青光眼（POAG）的发病机制，使其有可能实施有效的筛查和预防策略，并开发新的治疗方法。 虽然POAG具有显著的遗传性，但最近使用中等样本量的全基因组关联研究仅确定了少数具有中等效应大小的POAG相关基因。 这些结果表明，需要具有明确表型的大型数据集来充分描述POAG的遗传结构。 该建议将有效地利用现有的数据集来创建用于调查POAG遗传决定因素的大样本，其主要重点是鉴定有助于POAG相关定量内表型，杯盘比（CDR）的基因。 新出现的数据表明，CDR，即使是主观确定，是一个重要的成果，提供了宝贵的见解POAG的发病机制。 此前，我们成立了两个合作财团，为GWA研究提供了3，517例POAG病例和3，631例对照，NEIGHBOR财团（NEI青光眼人类遗传合作）和GLAUGEN研究（青光眼遗传学）。 这项建议的近期目标是：1）扩大NEIGHBOR和GLAUGEN联盟，创建NEIGHBORHOOD（NEIGHBOR遗传总体操作数据库）联盟和数据库，其中将包括总计4，652例POAG病例、16，909例CDR受试者和42，486例对照的协调基因型和表型数据，2）使用该增强的数据集进行荟萃分析，以鉴定影响CDR的新基因，以及有助于POAG的基因。 此外，这一建议将成为未来研究其他POAG相关性状和CDR和POAG的基因-基因和基因-环境相互作用的基础。 公共卫生相关性：原发性开角型青光眼（POAG）导致永久性视力丧失，是全球范围内具有公共卫生意义的疾病，影响数百万人。 原发性开角型青光眼的病因尚不清楚，缺乏有效的一级预防和治疗手段。 在这项提案中，我们的合作联盟将开发一个可操作的数据库，其中包含超过4600例POAG病例的表型和基因型信息，16，000例具有遗传性POAG内表型杯盘比（CDR）数据的个体，以及42例，000个对照，可用于识别POAG的危险因素，最终目的是阐明POAG的分子发病机制，实施有效的筛查和预防策略，并开发新的治疗方法。

DESCRIPTION (provided by applicant): Primary open angle glaucoma (POAG) is a significant cause of blindness worldwide. The etiology of POAG is poorly understood and primary prevention is not possible. Current treatments can slow but do not cure this progressive neuropathy. The overall goal of our research is to elucidate the pathogenesis of primary open-angle glaucoma (POAG) making it possible to implement effective screening and prevention strategies and to develop novel therapies. While POAG has a significant heritability, recent genome-wide association studies using moderate sample sizes have only identified a few POAG-related genes with modest effect sizes. These results suggest that large datasets with well-defined phenotypes are needed to fully delineate the genetic architecture of POAG. This proposal will efficiently use existing datasets to create a large sample useful for investigation o genetic determinants of POAG, with a primary focus of identifying genes contributing to the POAG-related quantitative endophenotype, cup-to-disc ratio (CDR). Emerging data suggests that CDR, even when subjectively ascertained, is an important outcome providing valuable insights into the pathogenesis of POAG. Previously we formed two collaborative consortia contributing 3,517 POAG cases and 3,631 controls for GWA studies, the NEIGHBOR consortium (NEI Glaucoma Human genetic collaboration) and the GLAUGEN study (Glaucoma Genetics). The immediate goals of this proposal are: 1) expand the NEIGHBOR and GLAUGEN consortia to create the NEIGHBORHOOD (NEIGHBOR Heritable Overall Operational Database) consortium and database, which will include harmonized genotype and phenotype data for a total of 4,652 POAG cases, 16,909 subjects with CDR and 42,486 controls~ and, 2) use this enhanced dataset to perform meta-analyses to identify novel genes influencing CDR, as well as genes that contribute to POAG. Additionally, this proposal will form the basis of future studies of other POAG related traits and gene-gene and gene-environment interactions for CDR and POAG. PUBLIC HEALTH RELEVANCE: Primary open angle glaucoma (POAG) causes permanent loss of vision and is a condition of public health significance worldwide, affecting millions of people. The etiology of POAG is poorly understood and effective means of primary prevention and curative therapies are not available. In this proposal, our collaborative consortium will develop an operational database housing phenotype and genotype information for over 4600 POAG cases, 16,000 individuals with data for the heritable POAG endophenotype cup-to-disc ratio (CDR), and 42,000 controls that can be used to identify risk factors for POAG with the ultimate goal of elucidating the molecular pathogenesis of POAG making it possible to implement effective screening and prevention strategies and to develop novel therapies.